Synthesis of (-)-chaetominine

Article abstract of DOI:10.1021/ol7022483

(Chemical Equation Presented) The tricyclic hydroxy imidazolidinone was converted to chaetominine in seven steps in 22% overall yield. The key step was the construction of the δ-lactam by heating an amino ester with a catalytic amount of DMAP in toluene a

Full text of DOI:10.1021/ol7022483

ORGANIC
LETTERS
2007
Vol. 9, No. 23
4913-4915
Synthesis of (−)-Chaetominine
Barry B. Snider* and Xiaoxing Wu
Department of Chemistry MS 015, Brandeis UniVersity,
Waltham, Massachusetts 02454-9110
snider@brandeis.edu
Received September 13, 2007
ABSTRACT
The tricyclic hydroxy imidazolidinone was converted to chaetominine in seven steps in 22% overall yield. The key step was the construction
of the -lactam by heating an amino ester with a catalytic amount of DMAP in toluene at reflux.
δ
Tan and co-workers recently isolated chaetominine (1), an
alkaloid with a novel skeleton from Chaetomium sp. IFB-
E015, an endophytic fungus found on apparently healthy
Adenophora axilliflora leaves (see Figure 1).1 The structure
Chaetominine (1) is a modified tripeptide alkaloid contain-
ing D-tryptophan, L-alanine, anthranilic acid, and formic acid.
Chaetominine is very closely related to the fumiquinazoline
alkaloids such as fumiquinazolines A (2) and B (3), which
are tetrapeptide alkaloids containing D-tryptophan, L-alanine,
anthranilic acid, and a second alanine instead of the formic
acid of chaetominine. We recently reported efficient syn-
theses of (-)-fumiquinazolines A, B, C, E, H, and I.2 The
key step in the syntheses is the Buchwald palladium-
catalyzed cyclization of iodocarbamate 4, which provided
tricycle 5 in 64% yield (see Scheme 1). Oxidation of tricycle
5 with oxaziridine 6 in MeOH followed by reduction with
NaBH4 in HOAc afforded hydroxy imidazolidinone 7 in 51%
yield. Treatment of 7 with silica gel resulted in cyclization
to form lactone 8, which was then elaborated to fumiquinazo-
lines A, B, C, and E.2
Deprotection of the Cbz group of 7, formation of the
δ-lactam, deprotection of the Troc group, and construction
of the quinazolinone should provide a short synthesis of
chaetominine (1). However, our earlier studies indicated that
formation of the δ-lactam might not be straightforward.
Hydrogenolysis of the Cbz group of 7 afforded amino alcohol
9, which was treated with silica gel in CH2Cl2 to give lactone
10 in 81% yield from 7.2 Hydrogenolysis of the Cbz group
of 7 could be accomplished without hydrogenolysis of the
tertiary benzylic alcohol, but hydrogenolysis of Cbz lactone
Figure 1. Structures of chaetominine (1) and fumiquinazolines A
(2) and B (3).
was determined by both spectroscopic analysis and single-
crystal X-ray diffraction analysis. The absolute stereochem-
istry was assigned as shown based on the release of L-alanine
on acidic hydrolysis. Chaetominine is more active against
human leukemia K562 (21 nM) and colon cancer SW1116
(28 nM) cell lines than 5-fluorouracil.
(1) Jiao, R. H.; Xu, S.; Liu, J. Y.; Ge, H. M.; Ding, H.; Xu, C.; Zhu, H.
L.; Tan, R. X. Org. Lett. 2006, 8, 5709-5712.
(2) Snider, B. B.; Zeng, H. J. Org. Chem. 2003, 68, 545-563.
10.1021/ol7022483 CCC: $37.00
© 2007 American Chemical Society
Published on Web 10/18/2007

Scheme 1. Synthesis of Imidazolidinone 7
Scheme 2. Synthesis of (-)-Chaetominine (1)
8 resulted in reductive cleavage of the benzylic lactone as
well as the Cbz group.2
We explored a variety of approaches to form the desired
δ-lactam from amino alcohol 9. These invariably led to
complex mixtures or the undesired lactone 10. Eventually,
we concluded that protection of the alcohol was necessary.
Reaction of 7 with TESOTf and 2,6-lutidine in CH2Cl2 at
0-25 °C provided TES ether 11 in 80% yield (see Scheme
2).3 Hydrogenolysis with 1 atm of H2 and 10% Pd/C afforded
the desired amino ester 12 in only 56% yield, suggesting
that cleavage of the TES group or hydrogenolysis of the
OTES group was occurring. Use of Pd(OH)2 as catalyst or
transfer hydrogenation did not improve the yield. We were
unable to prepare more hindered silyl ethers of 7 in
acceptable yield, so we proceeded with compound 12.
Lactamization of amino ester 12 was also challenging but
was eventually accomplished to give 13 in 79% yield by
heating 12 in toluene containing a catalytic amount of DMAP
for 3 days at reflux in a sealed tube.4 Lactam 13 was
contaminated with about 5% of two compounds that are
probably diastereomers of 13. Use of 6 equiv of Et3N instead
of catalytic DMAP gave a lower yield of 13.5
Deprotection of the Troc group of 13 without cleavage of
the TES ether was accomplished with Zn in 1:1 MeOH/
HOAc to give amine 14 in 88% yield. Reaction of amine 14
with isatoic anhydride in benzene at reflux6 afforded amino
amide 15 in 82% yield. Reaction of 15 with excess triethyl
orthoformate and a catalytic amount of TsOH in benzene at
reflux6 provided TES-chaetominine (16) in 83% yield.
Cleavage of the TES group in 1:19 concentrated HF/CH3CN7
for 7 h at 25 °C provided chaetominine (1) in 89% yield.
The yields were improved if intermediates were not purified.
The four-step conversion of 13 to 1 proceeded in 62% overall
yield when only amino amide 15 was purified.
1
The H and 13C NMR, IR, CD, and mass spectra of
synthetic 1 are identical to those reported by Tan.1 H14, H19,
H25, C13, C14, C17, C18, and C23 are very broad as noted by
Tan. He attributed this to slow inversion of an sp3 nitrogen
in the quinazolinone ring. We think that this is probably a
result of slow rotation about the C14-N bond. Similar
broadening in the 1H and 13C NMR spectra of TES ether 16
also results from slow rotation about this bond.
Tan noted that chaetominine (1) was unstable in acid and
recrystallized it from MeOH at room temperature.1 We found
that heating 1 in MeOH at reflux for 5 h afforded a 1:1
(3) Kamenecka, T. M.; Danishefsky, S. J. Chem.sEur. J. 2001, 7, 41-
63.
(4) For conversion of amino esters to lactams with DMAP in toluene at
reflux, see: (a) Gramberg, D.; Robinson, J. A. Tetrahedron Lett. 1994, 35,
861-864. (b) Gramberg, D.; Weber, C.; Beeli, R.; Inglis, J.; Bruns, C.;
Robinson, J. A. HelV. Chim. Acta 1995, 78, 1588-1606.
(5) For conversion of amino esters to lactams with Et3N in toluene at
reflux, see: (a) Dumas, J.-P.; Germanas, J. P. Tetrahedron Lett. 1994, 35,
1493-1496. (b) Tong, Y.; Olczak, J.; Zabrocki, J.; Gershengorn, M. C.;
Marshall, G. R.; Moeller, K. D. Tetrahedron 2000, 56, 9791-9800.
(6) Nakagama, M.; Taniguchi, M.; Sodeoka, M.; Ito, M.; Yamaguchi,
K.; Hino, T. J. Am. Chem. Soc. 1983, 105, 3709-3710.
(7) Newton, R. F.; Reynolds, D. P.; Finch, M. A. W.; Kelly, D. R.;
Roberts, S. M. Tetrahedron Lett. 1979, 20, 3981-3982.
4914
Org. Lett., Vol. 9, No. 23, 2007

significantly increases the strain. No reaction occurs on
heating 11 in MeOH at reflux for 5 h, which supports the
hypothesis that the ring strain of the tetracyclic ring system
of chaetominine makes the imidazolidinone much more
susceptible to cleavage. Relief of ring strain in 1 could be
achieved by opening either the δ-lactam or the γ-lactam with
MeOH. The inherently greater reactivity of an N-aryl lactam
than that of an N-alkyl lactam may be at least partially
responsible for the selective opening of the γ-lactam. The
enhanced reactivity of the strained γ-lactam ring of 1 likely
plays a role in its biological activity.
Scheme 3. Interconversion of Chaetominine (1) and Amino
Ester 17
The strain of the tetracyclic ring system is likely respon-
sible for the cyclization of amino alcohol 9 with SiO2 in
CH2Cl2 to give amino lactone 10 rather than the desired
hydroxy lactam. However, it is not clear whether this is a
result of kinetic or thermodynamic control. We therefore
cleaved the TES ether of 13 to give hydroxy lactam 19,
which is an isomer of amino lactone 10. Unfortunately, both
amino lactone 10 and hydroxy lactam 19 decomposed on
heating in toluene containing a catalytic amount of DMAP
so that we were unable to determine the relative stability of
amino lactone 10 and hydroxy lactam 19 (see Scheme 4).
mixture of 1 and amino ester 17 (see Scheme 3). Chroma-
tography afforded a 6:1 mixture of 17 and 1, which was
converted to 1:1 mixture on heating in MeOH at reflux for
5 h. The conversion of 17 back to 1 establishes that the
reaction is reversible and that the 1:1 mixture is at equilib-
rium. There are two lactams in chaetominine (1), and either
one could be opened by MeOH to give a methyl ester. The
1H NMR spectrum of 17 shows two protons at δ 6.85 (dd,
1, J ) 7.6, 7.6 Hz) and 6.74 (d, 1, J ) 7.6 Hz), whereas the
furthest upfield aromatic hydrogen of chaetominine absorbs
at δ 7.24. The upfield shift establishes that the N-acylindoline
was cleaved to give an indoline, which has the expected
upfield absorptions8 for the protons ortho and para to the
nitrogen.
Scheme 4. Lactone 10 and Lactam 19 Do Not Interconvert
with DMAP in Toluene at Reflux
The facile cleavage of the γ-lactam ring of 1 on heating
in MeOH is not typical of γ-lactams and may result from
the strain present in the tetracyclic core of chaetominine (1).
The crystallographic data support this analysis. The C9-N1-
C10dO and C2-N1-C10dO torsion angles in 1 are 37.8 and
175.0°, respectively (see Figure 2).1 In the simple tricyclic
In conclusion, fumiquinazoline intermediate 7 has been
converted to chaetominine (1) in seven steps in 22% overall
yield. The key step is the cyclization of amino ester 12 with
catalytic DMAP in toluene at reflux to give δ-lactam 13 in
79% yield.
Acknowledgment. We thank the NIH (GM50151) for
generous financial support.
Supporting Information Available: Full experimental
details and copies of 1H and 13C NMR spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
Figure 2. Torsion angles in the crystal structures of 1 and 18.
OL7022483
(8) For similar NMR spectra of related indolines, see ref 3 and: (a)
Giorgio, E.; Tanaka, K.; Verotta, L.; Nakanishi, K.; Berova, N.; Rosini, C.
Chirality 2007, 19, 434-445. (b) Sunazuka, T.; Shirahata, T.; Tsuchiya,
S.; Hirose, T.; Mori, R.; Harigaya, Y.; Kuwajima, I.; Ohmura, S. Org. Lett.
2005, 7, 941-943.
(9) He, F.; Foxman, B. M.; Snider, B. B. J. Am. Chem. Soc. 1998, 120,
6417-6418.
model 18, the torsion angles are 21.9 and 177.2°, respec-
tively.9 The torsion angles should be 0 and 180°, respectively,
in an unstrained amide. The deformation from 21.9° in 18
to 37.8° in 1 suggests that the introduction of the δ-lactam
Org. Lett., Vol. 9, No. 23, 2007
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